Commentary on ‘Implications of the SARS-CoV-2 subvariants BA.4 and BA.5’
Authors: Elnaz Khani, Taher Entezari-Maleki
Journal: International Journal of Surgery (2023)

We read with interest Rahimi and Talebi Bezmin Abadi’s study about the implications of the severe acute respiratory syndrome coronavirus 2 subvariants BA.4 and BA.51. As they mentioned, the latest mutations in the severe acute respiratory syndrome coronavirus 2 spike gene caused the latest coronavirus disease 2019 variants of concern. The Omicron (B.1.1.529) clade had the greatest amino acid mutations compared to the previous variants2. Recent evidence showed that other key mutations in the Omicron variant, particularly Δ69-70, F486V, L452R, and reversion in position 493 (R493Q), made BA.4 and BA.5 subvariants of concern3. The pathway by which Δ69-70 mutation in the N-terminal domain contributes to antibody evasion is not fully understood but makes BA.4 and BA.5 subvariants undetectable by the S-gene target failure test4. The F486V mutation resulting from the substitution of valine, an aliphatic amino acid with a smaller volume, instead of aromatic amino acid phenylalanine, in the spike receptor-binding motif, can be classified as the immune escape mutation and probably decrease the effectiveness of human neutralizing antibodies (NAb), including class 1 VH3-53-encoded short third complementarity determining regions of heavy chain variable (CDRH3) NAb and class 2 VH3-53-encoded long CDRH3 NAb5,6. The L452R mutation caused by the substitution of arginine instead of leucine increases the binding ability of the virus to the angiotensin-converting enzyme 2 receptors. Moreover, this mutation is associated with an escape from class 2 and class 3 antibodies, a decrease in the effectiveness of HLA-A24-restricted cellular immunity, and increased fusogenicity7. Hence, it is expected that compared to previous subvariants, BA.4 and BA.5 have a much higher ability to infect pulmonary alveolar epithelial cells. In fact, the virus’s cellular tropism has changed to affect the lower respiratory tract more severely. Besides L452R effects on increased virus-mediated cell–cell fusion, the formation of syncytia and immune evasion leads to lymphocyte internalization, increasing the risk of lymphopenia in patients infected with BA.4 and BA.5 subvariants8. Hence, inhibitors of anoctamin (also known as TMEM16), such as niclosamide and interferon-inducible transmembrane protein inducers like mycophenolic acid, might prevent syncytia formation9–11. However, more data are required for a better evaluation of their effectiveness. The unique effect of the L452R mutation on the metabolic reprogramming of host cells, similar to the Warburg effect in cancer cells, increases anaerobic glycolysis in the infected cell, providing the energy required for further replication12. Indeed, reinfection and vaccine breakthrough infection is quite obvious so far. Clinical evidence also showed that hybrid immunity caused by BA.1 infection in a person vaccinated with a booster shot could not prevent BA.4 and BA.513. Regarding the reversion that occurred at position 493, this mutation probably improves the receptor affinity and increases the fitness of the subvariants3. Unlike BA.1 and BA.2, the cell entry of the BA.5 variant was shown to rely on the transmembrane protease serine 2 (TMPRSS2), which has a high expression in the lower respiratory tract. Considering the crucial role of TMPRSS2 in spike glycoprotein cleavage at the S1/S2 site, its inhibition in the early stages of the disease might attenuate the risk of lung involvement14. Consequently, these mutations cause higher fitness for the virus, raising concerns about developing nirmatrelvir and ritonavir (Paxlovid)-resistant 3-chymotrypsin-like protease (3CLPro) mutant15. Hence, booster doses with vaccines designed based on the dominant variants should be considered. Ethical approval This article does not require any human/animal subjects to acquire such approval. Sources of funding None. Author contribution E.K.: conceptualization, writing – original draft. T.E.M.: writing – review and editing, supervision. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) None. Guarantor All authors.